Can limiting protein intake (or other selective nutrient depletion) induce autophagy?
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A critical element in the mechanisms that regulate autophagy is the cell’s ability to sense changes in cellular levels of acetyl CoA, an end product of nutrient metabolism. When mice or humans are deprived of nutrients, protein deacetylation – which often coincides with autophagy – begins to occur on the organism-wide level. Whether removal of single nutrients induces the same changes is not known. In this clip, Dr. Guido Kroemer describes the interplay between protein deacetylation and autophagy.
- Rhonda: I know that if you take cultured cells in a dish and you just...you're doing some, you know, specific nutrient withdraw, you withdraw amino acids when you withdraw glucose, or you withdraw glutamine, you can induce autophagy. But in the whole organism, for example, in mice and in humans, ultimately, you know, can you just limit your protein intake for a week and induce autophagy even in the presence of a normally caloric diet where you're still getting enough energy.
- Dr. Kroemer: That's a good question. We have never tested to selective completion of one or the other nutrient, I suppose that this would work, because protein depletion may affect a newer endocrine factors like insulin growth factor that, at the end, will, due to its depletion, decrease the transport of glucose into the cells. And hence, stimulate autophagy. But it has not been tested thoroughly in mice. What we usually do is we starve mice and sometimes human volunteers completely from any kind of caloric uptake, and in this case, we do see, at the whole body level, that in all major cell types, perhaps with the exception of the brain that is somehow buffered against this effect, protein deacetylation occurs mostly in the cytoplasm.
- Rhonda: And that's a biomarker of autophagy, you would say?
- Dr. Kroemer: Well, it's too early to say that it is a surrogate or proxy of autophagy. So far, we have not been able to dissociate the two phenomenon, autophagy and protein deacetylation, in the response to nutrients. However, when you induce autophagy by pharmacological tricks, such as cell permeable peptides that dissociates an inhibitory interaction between a Golgi protein and Beclin 1. You can induce autophagy without that protein deacetylation would occur before. And similarly, when you give chemical inhibitors of mTOR like rapamycin or the rapalogs, there's also no protein deacetylation. So, you can induce autophagy without protein deacetylation which means that the proxy would be imperfect. So we do have a system to measure autophagy which is relatively easy to be used in experimental systems which is the study of the redistribution of LC3 and other members of the same family that are usually diffusely distributed all over the cell, mostly in the cytosol, and then we'll aggregate or redistribute towards autophagosomes and autolysosomes. So they acquire a punctate distribution small dots in the cytoplasm and these dots can be seen by fluorescence microscopy if LC3 is labeled by immunofluorescence or when it is fused with green fluorescent protein or similar biosensors.
An intracellular degradation system involved in the disassembly and recycling of unnecessary or dysfunctional cellular components. Autophagy participates in cell death, a process known as autophagic dell death. Prolonged fasting is a robust initiator of autophagy and may help protect against cancer and even aging by reducing the burden of abnormal cells.
The relationship between autophagy and cancer is complex, however. Autophagy may prevent the survival of pre-malignant cells, but can also be hijacked as a malignant adaptation by cancer, providing a useful means to scavenge resources needed for further growth.
A measurable substance in an organism that is indicative of some phenomenon such as disease, infection, or environmental exposure.
The aqueous component of the cytoplasm of a cell, within which various organelles and particles are suspended.
One of the most abundant non-essential amino acids in the human body. Glutamine plays key roles in several metabolic functions, including protein and glutathione synthesis, energy production, antioxidant status, and immune function. In addition, it regulates the expression of several genes. Although the body can typically produce all the glutamine it needs, during periods of metabolic stress it must rely on dietary sources of glutamine such as meats, fish, legumes, fruits, and vegetables.
A naturally occurring substance capable of stimulating cellular growth, proliferation, healing, and differentiation. Growth factors typically act as signaling molecules between cells. Examples include cytokines and hormones that bind to specific receptors on the surface of their target cells.
A peptide hormone secreted by the beta cells of the pancreatic islets cells. Insulin maintains normal blood glucose levels by facilitating the uptake of glucose into cells; regulating carbohydrate, lipid, and protein metabolism; and promoting cell division and growth. Insulin resistance, a characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response, which can lead to high blood glucose levels.
An enzyme that participates in genetic pathways that sense amino acid concentrations and regulate cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. mTOR integrates other pathways including insulin, growth factors (such as IGF-1), and amino acids. It plays key roles in mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain. It is dysregulated in many human diseases, such as diabetes, obesity, depression, and certain cancers. mTOR has two subunits, mTORC1 and mTORC2. Also referred to as “mammalian” target of rapamycin.
Rapamycin, the drug for which this pathway is named (and the anti-aging properties of which are the subject of many studies), was discovered in the 1970s and is used as an immunosuppressant in organ donor recipients.
A chemical reaction that removes an acetyl functional group from a chemical compound. The presence of the acetyl functional group plays an important role in the synthesis, stability and localization of about 85% of human proteins.[1] During fasting, falling acetyl CoA levels in the cytosol initiate protein deacetylation and initiates autophagy. In general, protein deacetylation, whether from so-called caloric restriction mimetics or nutrient deprivation, is an important general inducer of autophagy.
- ^ Arnesen, Thomas; Van Damme, Petra; Martinho, Rui Gonçalo; Helsens, Kenny; Hole, Kristine; Pimenta-Marques, Ana, et al. (2011). NatF Contributes To An Evolutionary Shift In Protein N-Terminal Acetylation And Is Important For Normal Chromosome Segregation PLOS Genetics 7, 7.
A compound initially developed as an antifungal agent. This use was abandoned, however, when it was discovered to have potent immunosuppressive and antiproliferative properties due to its ability to inhibit one of the complexes of mTOR (mTORC1). Rapamycin has since shown interesting lifespan extension properties in animals.
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